Accession Number : ADA613706


Title :   Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)


Descriptive Note : Final rept. 15 Sep 2012-14 Sep 2014


Corporate Author : BRIGHAM AND WOMENS HOSPITAL BOSTON MA


Personal Author(s) : Yu, Jane


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a613706.pdf


Report Date : Dec 2014


Pagination or Media Count : 8


Abstract : Lymphangioleiomyomatosis (LAM) is a progressive neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically due to TSC2 mutations resulting in mTORC1 activation in proliferative smooth muscle-like cells in the lung. The female predominance of LAM suggests that estradiol contributes to disease development. Metabolomic profiling identified an estradiolenhanced prostaglandin biosynthesis signature in Tsc2-deficient cells, both in vitro and in vivo. Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was also increased at baseline in TSC2-deficient cells, and was not affected by rapamycin treatment. However both Torin 1 treatment and Rictor knockdown, led to reduced COX-2 expression and phospho-Akt-S473. Prostaglandin production was also increased in TSC2-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had significantly higher serum prostaglandin levels than healthy women. 15-epi-lipoxin-A4 was identified in exhaled breath condensate from LAM subjects and was increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of LAM patient-derived cells in a dose-dependent manner. Targeting COX-2 and prostaglandin pathways may have therapeutic value in LAM and TSC-related diseases, and possibly in other conditions associated with mTOR-hyperactivation.


Descriptors :   *LUNG , *RESPIRATORY SYSTEM , ACTIVATION , BASE LINES , BLOOD SERUM , CELLS(BIOLOGY) , DESTRUCTION , DISEASES , ESTROGENS , FAILURE , HORMONES , IN VITRO ANALYSIS , IN VIVO ANALYSIS , MODELS , NEOPLASMS , ORDER DISORDER TRANSFORMATIONS , PATIENTS , PRODUCTION , PROSTAGLANDIN , REDUCTION , SALICYLIC ACIDS , TARGETING , THERAPY


Subject Categories : Medicine and Medical Research


Distribution Statement : APPROVED FOR PUBLIC RELEASE